GELATIN AND MATERIALS OTHER
THEN GELATIN USED FOR CAPSULES FORMULATION
Gelatin is a substantially pure protein
food ingredient, obtained by the thermal denaturation of collagen, which is the
structural mainstay and most common protein in the animal kingdom. Gelatin is a
water soluble protein aqueous substance prepared by processes, which involve
the destruction of the tertiary, secondary and to some extent the primary
structure of native collagens specifically by the partial hydrolysis of
collagen derived from the skin, white connective tissue and bones of animals.
Gelatin is a high molecular weight polypeptide and an important hydrocolloid,
which has proved popular with the general public and finds its uses in a wide
range of food products largely because of its gelling and thickening
properties. Cattle bones, hides, pig skins, fish and recently insects are the
main commercial sources of gelatine. Many foods use gelatine as source for
texture and binding agent, gelatine from insect can be used to produce ice
cream by using 0.5% insect’s gelatine and compared with that made using 0.5%
commercial gelatine as stabilizing agent.
1.
Reasons
for choosing gelatin
·
It is non toxic widely used in foodstuff
and acceptable for use worldwide.
·
It is readily soluble in biological
fluid at body temp.
·
It has a good film forming properties
with flexibility.
2.
Extraction
of gelatin
Gelatin
is a heterogeneous derived from hydrolytic extraction of animals collagen
obtained from animals bones or hide protion from dry bone or pork skin.
TYPE OF GELATIN:
·
TYPE
A
gelatin is derived from an acid-treated precursor and exhibits an isoelectric
point in the region of pH 9. It is manufactured mainly from pork skin.
·
TYPE B gelatin is derived from an
alkali-treated precursor and has its isoelectric zone in the region of pH 4.7. It is manufactured mainly from animal
bones.
PRODUCTION OF GELATIN:
On a
commercial scale, gelatin is made from by-products of the meat and leather
industry, mainly pork skins, pork and cattle bones, or split cattle hides.
Contrary to popular belief, horns and hooves are not commonly used. The raw
materials are prepared by different curing, acid, and alkali processes which
are employed to extract the dried collagen hydrolysate. The entire process
takes several weeks.
Degreased dried crushed
bone Pork skins
Acid Treatment
Chopping
Lime treatment
Water wash
Washing
Acid treatment
Acid treatment
Washing
Multiple hot
water extraction
Filtration
Ion exchange
deionization
Evaporation
Filtration
 Final concentration
Sterilization
Polish
filtration
Chilling to set pointExtrusion
Drying
Milling
Blending and
Packaging
|
Figure.1 Gelatin Production Processes
Criteria
to check the properties of gelatin
Bloom
strength:
It is a measure of gel rigidity. It is
defined as weight in grams required to push a standard plunger 4 mm into a
standard gel that has been maintained at 100 C for 17 hours.
The gelatin used in hard gelatin capsule
manufacture is of a higher bloom strength 200-250g than that used for soft
gelatin capsules 150g.
Viscosity:
It controls the thickness of shell and
it is the measure of molecular chain length. A gel containing 6.66% w/v of
gelatin is prepared and viscosity is measured at 600 C. low
viscosity, high bloom gelatin are used for encapsulating hygroscopic solid/
liquids.
Iron
contents:
Should not exceed 15 ppm.
TYPE
OF GELATIN CAPSULES:
There are two types of gelatin capsules:
1. HARD GELATIN CAPSULE:
The hard capsule is also called “two piece”.
it consists of two pieces in the
form of small cylinders closed at one end, the shorter piece is called the
“cap” which fits over the open end of the longer piece, called the “body” and
is then filled with the drug.
2. SOFT GELATIN CAPSULES:
The soft gelatin capsule is also called as
“one piece”. Capsules are available in many sizes to provide dosing
flexibility. Soft capsules are formed in a single piece.
SOFT GELATIN CAPSULES:-
A soft gelatin capsule is a
solid capsule (outer shell) surrounding a liquid or semi-solid centre (inner
fill), as shown in figure 2. An active ingredient can be incorporated into the
outer shell, the inner fill, or both.
Soft capsules are a single-unit solid
dosage form, consisting of a liquid or semi-solid fill enveloped by one piece
sealed elastic outer shell. The amount of drug or extract together with
adjuvant is enclosed within a globular, oval or other shape of a soft shell1.
Soft gelatin capsules (softgel) offer the possibility of delivering a liquid in
a solid oral dosage form. The softgel can contain the active ingredient in
solution, suspension or emulsion, which will inherently lead to better
absorption of the active ingredient as compared with delivery in a tablet or as
a powder.
Figure.2
Soft gelatin capsules
Soft gelatin capsules1 (referred to as
soft elastic gelatin capsules, liquid gels or softgels) are a unique drug
delivery system that can provide distinct advantages over traditional dosage
forms such as tablets, hard gelatin capsules and liquids. However due to
economic, technical and patent constraints there are relatively a few
manufacturers of softgels in the world. Softgel is a hermetically sealed,
one-piece capsule with a liquid or semisolid fill. The softgel consists of two
major components, the gelatin shell and the fill. In the finished product
gelatin shell is primarily composed of gelatin, plasticizer and water. The fill
material can include a wide variety of vehicles and can either be a solution or
a suspension. Softgels may be coated with suitable exterior coating agents such
as Cellulose acetate phthalate (CAP) to obtain enteric release of encapsulated
material. The standard softgel shape of oral pharmaceutical products is oval,
oblong and round, though softgels can be manufactured in many shapes.
Soft gelatin capsules offer the
possibility of delivering a liquid in a solid oral dosage form. The soft
gelatin capsules can therefore contain the active ingredient in solution,
suspension or emulsion, which will inherently lead to better absorption of the
active ingredient as compared with delivery in a tablet or as a powder.
Softgels are therefore the ideal solution –and sometimes the only solution –
for delivery of compounds with poor oral bioavailability. Other properties that
make softgels a useful and frequently applied dosage form include their
aesthetic properties and ‘swallowability’, their tamper-resistance, their
protection of the active ingredient from light and oxidation, their
taste-masking of ingredients and their masking of unpleasant odours of ingredients.
ADVANTAGES
OF SOFT GELATIN CAPSULES:
§ Ease
of use - easy to swallow, no taste, unit dose delivery, temper proof.
§ Improved
drug absorption and possible bioavailability advantages.
§ Avoids
dust handling problems during manufacture and better operator safety.
§ Dose
uniformity for low-dose drugs.
§ Good
product stability (drugs are protected against oxidative degradation by lipid
vehicles and gelatin shells).
§ Accommodates
a wide variety of compounds filled as a semisolid, liquid, gel or paste.
§ Wide
variety of colors, shapes and sizes.
§ Immediate
or delayed drug delivery-can is used to improve bioavailability by delivering
drug in solution or other absorption enhancing media.
§ Reduced
dustiness; lack of compression stage in manufacture.
§ Possible
reduced gastric irritancy compared to tablets and hard shell capsules.
DISADVANTAGES OF SOFT GELATIN CAPSULES:
§ Soft
gelatin capsules are not easily prepared except on a large scale and with
specialized equipment.
§ They
are an expensive dosage form, when compared with direct compression
tablets.
§ There
is a more intimate contact between the shell and its liquid contents than
exists with dry-filled hard gelatin capsules, which increases the possibility
of interactions.
§ Not
adaptable to incorporation of more than one kind of fill into the same capsule
(compare with hard shell capsules)
§ Stability
concerns with highly water soluble compounds, and compounds susceptible to
hydrolysis, Limited choices of excipients/carriers compatible with the gelatin Sensitive to heat and moisture, Dietary
restrictions.
FORMULATION OF SOFT GELATIN
CAPSULES:
PLASTICIZERS:
These are used to make the
softgel shell elastic and pliable. They usually account for 20-30%. The most
common plasticizers used in softgels is glycerol, although sorbitol and
propylene glycol-400 are used frequently often in combination with glycerol. The
amount and choice of the plasticizer contribute to the hardness of the final
product and may even affect its dissolution or disintegration characteristics,
as well as its physical and chemical stability. One of the most important
aspect of softgel formulation is to ensure that there is minimum interaction or
migration between the liquid fill matrix and the soft gel shell. The choice of
plasticizer type and concentration is important in ensuring optimum
compatibility of the shell with the liquid fill matrix.
WATER:
The other essential
component of the soft gel shell is water. Water usually accounts for 30-40 % of
the wet gel formulation and its presence is important to ensure proper
processing during gel preparation and softgel encapsulation. In dry gels the
equilibrium water content is typically in the range 5-8% w/w, which represents
the proportion of water that is bound to the gelatin in the soft gel shell.
This level of water is important for good physical stability, because in harsh
storage conditions softgels will become either too soft and fuse together, or
too hard and embrittled.
COLORANTS/OPACIFIERS:
Colorants
can be either synthetic or natural, and are used to impart the desired shell
colour for product identification. An opacifier, usually titanium dioxide may
be added to produce an opaque shell when the fill formulation is a suspension,
or to prevent photo degradation of light-sensitive fill ingredients. Titanium
dioxide can either be used alone to produce a white opaque shell or in
combination with pigments to produce a coloured opaque shell.
PRESERVATIVES:
Preservatives
are used for preserve the drug medicament from the microbes. It is used about
0.2% concentration of total drug medicament. Methyl paraben and propyl paraben
is mainly used as preservative.
FLAVOURING AGENTS:
Flavouring
agents is used for the taste masking. Ethyl vanillin, essential oils, and
different sugar mainly sucrose is also used as flavouring agent.
SOFT GELATIN CAPSULE
MANUFACTURING:
Following
methods are used:
1.
Plate process:
2. Rotary die process:
3.
Reciprocating
die process:
4. Accogel process:
5. Seamless gelatin capsules:
1. Plate process:
In this process a warmed
sheet of gelatin sheet is placed over a die plate having a number of depression
or moulds or numerous die pockets. The sheet is drawn into these depressions or pockets by applying
vacuum. A measured quantity of liquid medicament is pour over it. Over this
another plate of the mould is placed and the pressure is then applied to the
combine plate. The capsules are then simultaneously shaped, filled, sealed and
cut into individual units. This method is uses for small scale preparation of
soft gelatin capsules. It has 20-40% of net moisture content.
2. Rotary die process:
Before encapsulation process takes
place, there are two basic processes
Production of gel mass
which provide the soft gel shell:
The gel
mass is prepared by dissolving the gelatin in water approximately at 80ºC and under vacuum,
followed by addition of plasticizer. Once the gelatin is fully dissolved other
components such as color, opacifier, flavours and preservatives may be added.
The color is compared with the standard. Then the temperature maintained at
57-60ºC in melting tank. The hot gel mass is then supplied to the
encapsulation machine through heated transfer pipes by a casting method that
forms two separate gelatin ribbons. The gelatin mass is fed by gravity to a
metering device which controls the flow of mass on to air heated (13-14ºC) rotating drums. Gelatin ribbons are
produced. During the casting process the gelatin pass through the sol gel transformer
and the thickness of each ribbon is controlled to ±0.1 mm. The thickness
is checked regularly during the process. The ribbon of 0.022-0.045 inches but
for most capsules it is between 0.025-0.032 inches. The two gel ribbons are
then carried through rollers (at which a small quantity of vegetable oil
lubricant is applied) and onwards to the rotatory die encapsulation. Each
ribbon provide one-half of the softgel.
Fill
matrix:
The liquid fill matrix containing the active
drug substance is manufactured separately from preparation of molten gel.
Manufacture of the active fill matrix involves dispersing or dissolving the
drug substances in the non-aqueous liquid vehicle using conventional mixer
homogenizers. They also break up the agglomerates of solids. Oxygen sensitive
drugs are protected by mixing under vacuum and or inert gas or by addition of
antioxidant.
Schematic
diagram or rotatory die:
This machine has two,
side-by-side cylinders in each of which half-moulds are cut. These cylinders,
like the rollers of a mangle, rotate in contrary direction and as they are
mirror images the moulds come together precisely during rotation. Two ribbons
of gelatin are fed between the rollers and, just before the opposing rollers
meet, jets of medicament press the gelatin ribbon into the moulds, filling each
half. The moment of pressure follows, immediately sealing the two halves
together to form a capsule. These rotary machines are capable of producing
between 25000 and 30000 capsules an hour with an accuracy of dosage of
approximately ± 1 percent.
Encapsulation:
Liquid gelatin flowing from an overhead
tank is forward into continuous ribbon by the rotating drum and brought
together between twin rotating dies. The injection of liquid between the
ribbons, force the gel to expend and into the packets of dies, which govern the
size n shape of the softgels. The sealing of the capsules is done by mechanical
pressure on the die rolls and the heating of ribbons by the wedge. After
manufacture, it is subjected to IR drying and then they are separated on the
tray and stacked in funnel drier that supplies air at 20% relative humidity.
Figure 3, Schematic diagram or rotary die
machine
3. Reciprocating die process:
This is similar to rotary process, but is differ in
the actual encapsulating process. The gelatin ribbons are fed between a set of
vertical dies that continuously open and close to form the rows of the pockets
in the gelatin ribbons. These pockets are filled with the medication and are
sealed, shaped and cut out of the film as they progress through the machinery.
4. Accogel
process: (Stern Machine)
This is another rotary process involving the
measuring roll, a die roll and a sealing roll. The measuring roll rotates
directly over the die roll, and the pockets in the two rolls are aligned with
each other. The powder or granular fill material is held in the pockets of the
measuring roll under vacuum. A plasticized sheet is drawn in to the die pockets
of the die roll under vacuum. As the measuring roll and the die roll rotate,
the measured doses are transferred to the gelatin lined pockets of the die
roll. The continue rotation of the filled die converges with the rotating
sealing roll where second gelatin sheet is applied to form the other half of
capsule. The pressure developed between the both rolls seals and cut out of the
capsules.
5.
Seamless gelatin capsules:
It is a modern method for making soft
gelatin capsules takes advantage of the phenomenon of drop formation. The
essential part of the apparatus consists of two concentric tubes. Through the
inner tube flows the medicament and, through the surrounding outer tube, the
gelatin solution. The medicament, therefore, issues from the tube surrounded by
gelatin and forming a spherical drop. This is ensured by allowing the drop to
form in liquid paraffin in which the gelatin is insoluble. Regular induced
pulsations cause drops of the correct size to be formed, and a temperature of
4°C ensures that the gelatin shell is rapidly congealed. The capsules are subsequently
degreased and dried.
APPLICATIONS:
Ophthalmic
Soft Gelatin Capsules:
It
is very important that the ophthalmic ointments should be sterile and free from
irritant effect. Therefore they must be packed in such a manner that the
product remains sterile until whole of it is used up. The best method to keep
the preparation free from contamination during use is to pack it in single dose
containers. Now a day’s soft gelatin capsules are very commonly used for
filling ophthalmic ointments. These capsules are meant for single application
to the eye. Just before application, the capsule is punctured with a sterile
needle, the contents instilled into the eye and the shell discarded.
Chewable Soft Gelatin Capsules:
The chewable gelatin dosage form offers
excellent mouth feel and chewing experience as compared with other chewable
dosage forms. Chewable soft gels are particularly suitable for pediatric
populations, where swallowing whole tablets or capsules is often a problem, and
chewable tablets are often rejected. Consumer preference testing with Banner’s
new chewable gels showed that three out of four parents would buy this product
for their children data on file. This approach has resulted in a highly
acceptable end-product. Other taste-masking technologies can be combined with
the chewable softgel.
Controlled Release Soft Gelatin Capsules:
Banner’s scientists have developed a
controlled release technology that is able to achieve a large variety of
release patterns. The controlled release softgel can be applied to a wide range
of active molecules. Banner’s controlled release softgel technology uses a
lipid matrix in a standard softgel shell. Depending on the physicochemical
properties of the active molecule, an emulsion or a suspension is chosen as a
matrix. The result is an oral dosage form offering controlled release of the
active moiety, combined with all the benefits that the softgel dosage form
offers.
Enteric Coated Soft Gelatin Capsules:
In contrast to existing enteric dosage
forms, Banner’snew enteric softgel is not coated. The enteric features of the
dosage form reside in the shell itself. The result is a clear enteric dosage
form with the exact same appeal and patient benefits that the standard softgel
offers. Traditionally, enteric softgels were prepared by coating with enteric
polymers using traditional coating technology. Coating has its own
disadvantages such as unsuccessful adhesion of the enteric polymer onto the
soft gelatin shell due to the shell’s inherent flexible nature.
Gelatin-Free Soft Gelatin Capsules:
Gelatin-free soft capsules are made from
vegetable ingredients. They have all the advantages of standard softgels, but
do not contain gelatin. Gelatin free soft capsules are particularly suitable
for vegetarians or other populations that prefer non-animal products.
EVALUATION
OF SOFT GELATIN CAPSULES:
The Soft gelatin capsules should be subjected to following tests for
their standardization.
Disintegration Test:
For performing disintegration test on
capsules the tablet disintegration test apparatus is used but the guiding disc
may not be used except that the capsules float on top of the water. If hard
capsules float on the surface of the water, the discs may be added. One capsule
is placed in each tube which is then suspended in the beakers to move up and
down for 30 minutes. The beaker containing 600 ml water and temperature is 37
°C. Unless otherwise stated in the monograph. The capsules pass the test if no
residue of drug or other than fragments of shell remains on No. 10 mesh screen
of the tubes. If the disc is used, any residue remaining on its lower surface
should only consist of fragments of shell.
Dissolution:
It is done if capsules contain drug
which have limited solubility in gel fluid. The dissolution test is carried out
using the dissolution apparatus official in both the U.S.P. and N.F. The
capsule is placed in a basket formed from 40-mesh stainless steel fabric. A
stirrer is attached to the basket, and the basket is immersed in the
dissolution medium and caused to rotate at a specified speed. The dissolution
medium is held in a covered 1000 ml glass vessel and maintained at 37°C ± 0.5°C
by means of a suitable constant temperature water bath. The stirrer speed and
type of dissolution medium are specified in the individual monograph.
Weight Variation Test:
Twenty capsules are taken at random and
weighed. Their average weight is calculated, then each capsule is weighed
individually and their weight noted. The capsule passes the test if the weight
of individual capsule falls within 90-110% of the average weight. If this
requirement is not met, then the weight of the contents for each individual
capsule is determined and compared with the average weight of the contents. The
contents from the shells can be removed just by emptying or with the help of
small brush. The remainder contents are removed by washing with a suitable
solvent. After drying the shells, they are weighed and the content weights of
the individual capsules are calculated. The requirements are met if not more
than 2 of the differences are greater than 10 % of the average net content and
in no case the difference is greater than 25 %.
Moisture
Permeation Test:
By packing the dosage unit together with
color revealing desiccant pellet; exposing the packaged unit to known relative
humidity over a specified time, observing the desiccant pellet for color change
and comparing the pre and post weight of the packaged unit, moisture permeation
can be determined.
Capsule Stability:
This
inherent characteristic warrants a brief discussion of the effects of
temperature and humidity on these products, and points to the necessity of
proper storage and packaging conditions and to the necessity of choosing an appropriate
retail package. The variety of materials capsulated, which may have an effect
on the gelatin shell, together with the many gelatin formulations that can be
used, makes it imperative that physical standards are established for each product.
Materials other than gelatin
used for capsule formulation
Traditionally gelatin has been used almost
exclusively as shell forming mat of soft capsules. This is due to its legal
status its unique physical chemical properties namely
·
its oxygen impermeability
·
combination of film forming capability
·
thermoreversible sol gel formation
Despite three general adv. Gelatin has several
draw back that limits its use for soft capsule.
·
The animal source can be problem for
gelatin for certain consumers such as vegetarions or vellgious or ethnic
groups.
·
Since unmodified gelatin is prone to
cross linking when in contact with aldehydes solubility problems might be
expected with certain fill formulations.
·
Transparent low colour capsules are
difficult produce because of intrinsic Millard reaction on gelatin colour.
·
For low price health and nutrition
products pricing of commercially gelatin might be additional problem
Several
concepts based on synthetic polymers and plant derived hydrocolloids have been
described few gained commercial interact. This is due to fact that change in
capsule shell polymer material require. Legal approval and machinability
1. Use
of combination of iota carrageenan (12-24% w/w of dry shell) and modified
starch namely starch (30-60% w/w of dry shell as gelatin substitution).
Both components are accepted as food
additives with numbers. This allowing their use in health and nutrition
products. it can be formulated with conventional plasticizer such as glycerol,
sorbital etc. Water to from molten mass that can be extruded to set elastic
films on temp controlled casting drums.
2. Describe
formulation of soft capsules from potato starch (45-80% w/w) with specific
molecular weight distribution and amylopectin as glycerol. (>12% w/w) a
gllidant and disintegrant. Soft capsules are low price alternative to soft
gelatin capsules
3. Brown
1996 describe preferable use of PVA and optional use of some other material all
being film forming polymers that lack properties necessary for soft capsule
production PVA films according to invention may be composes of 70-75% w/w PVA,
10-15 w/w qlycer and 5% w/w, depending on degree of salvation PVA as an
optional less hyqroscopic this lead to soft capsule shells that are moistur that
soft gelatin capsule shells.
REFERENCES:
1.
Lachman
Leon, Lieberman Herbert A., et al “The Theory and Practice of Industrial
Pharmacy” 3rd edition, reprint1991, Published by Varghese publishing
house, Dadar Bombay, PP 398.
2. Ansel Howard C. Allen Loyed V., et al
“Pharmaceutical dosage forms and drug delivery system” 7th edition
2000, published by Lippincott Williams Philadelphia, PP 215.
3.
Bhatt Bhawna, Aggrawal S.S Pharmaceutical
Technology Delhi Institute of Pharmaceutical Science and Research Sector
– 3, Pushp Vihar New Delhi, PP 2, 18.
4.
L.L.
Augsburger, "Hard and Soft Gelatin Capsules," Chapter 11 in Modern
Pharmaceutics, 3nd Edition, G. Banker and C.T. Rhodes (Editors), Marcel Dekker,
Inc., New York,1995 PP 44, 47.
5.
Dr. Ali Javed, Dr. Kar RK, Dr. Alka
Ahuja “Dosage form Design”, 4th Edition, Published by Birla
Publication Pvt. Ltd. Delhi, PP 45,56.
6.
Softgel Technologies People, facilities
and technologies to deliver superior softgel
solutions.http://www.catalent.com/pharma/pdf/Softgel-Technologies-Oral-Technologies.
Accessed 2010/11/19.
7. Aulton Michael E., “Pharmaceutics the science
of dosage form design” 2nd Edition 2002, Published by Churchill
Livingstone, PP 527.
8. Remington – The Science and Practice of
Pharmacy, 21th edition, Volume – 1, published by Lippincott Williams
Philadelphia, PP 918, 923.
9.
Vegicaps Softgel Technologies People,
facilities and technologies to deliver superior softgel solutions. Copyright
2007 Catalent Pharma Solutions.
10.
Reich
G, Podczeck F and Jones BE. Formulation and physical properties of soft
capsules. 2004, - Medical, PP 272
11. Soft
gelatin manufacturing and Marketed preparation METHOXALONE softgels,
http://www.drugs.com/cdi/methoxsalen-soft-gelatin-capsules.html
12.
Gershanik T and Benita S.
Self-dispersing lipid formulations for improving oral absorption of lipophilic
drugs. European Journal of Pharmaceutics and Biopharmaceutics 2000, 50:
179-188
13. Martins
GZ, Souza CRF, Shankar TJ and Oliveira WP. Effect of process variables on fluid
dynamics and adhesion efficiency during spouted bed coating of hard gelatine
capsules. Chemical Engineering and Processing 2008, PP 2238–2246.
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